Currently, as an agent for curing respiratory distress syndrome (RDS) having a high mortality and acute respiratory distress syndrome (ARDS) causing severe respiratory disorders, there is applied an artificial pulmonary surfactant prepared from the pulmonary surfactant ingredient secreted from the bovine lung (e.g., “Pulmonary Surfactants Now” edited by Yoshida, S., Shinko Koeki Isho Shuppanbu, Tokyo, 1990; Riodan, J. R.: Molecular Basis of Disease: Pulmonary Surfactant, ed., Biochem. Biophys. Acta, 1408, 77-363, 1998).
The pulmonary surfactant is a lipid-protein complex produced by the aveolar cells and secreted therefrom, which is a substance essential for the maintenance of life and which plays a role for the pulmonary function by reducing the surface tension of the alveoli. The pulmonary surfactant present in the alveoli is composed of approximately 10% of proteins and lipid ingredients consisting mainly of phospholipids (e.g., Veldhuizen, R., et al., Biochim. Biophys. Acta, 1408, 90-108, 1998). The pulmonary surfactant contains the lipids, particularly a neutral phospholipid, i.e., L-(-phosphatidylcholine (PC) which amounts to 80.5% of the total lipids; while L-(-phosphatidylglycerol (PG) which is an acidic lipid amounts to 9.1%, L-α-phosphatidylinositol (PI) to 2.6% and cholesterol to 7.3%. In particular, it is to be noted that dipalmitoyi-L-α-phosphatidylcholine (DPPC) composed of saturated alkyl groups amounts to 47.7%, that is, approximately a half of the PC, and that this is considered to be a factor of preventing a collapse of the lung. It is rendered evident, however, that only the phospholipids including DPPC do not have any surfactant activity and small amounts of the protein ingredients are of importance (e.g., Robertson, B., and Halliday, H. L., Biochim. Biophys. Acta, 1408, 341-362, 1998).
There is an increasing necessity of the pulmonary surfactant for the application not only to RDS and ADRS but also to inflammatory pulmonary diseases such as pneumonia, etc. as well as to the mitigation of severe respiratory insufficiency symptoms caused by pulmonary cancers, etc., which are recently causing a rapidly increasing mortality. It is also known that the pulmonary surfactant substance is being secreted from the bronchus, and the substance is considered to play a role as an expectorant by preventing the block of the peripheral airway (e.g., Liu M., et al., J. Appl. Physiol., 71, 742-748, 1991). The pulmonary surfactant is expected to be applied to various diseases that require improvements in respiratory disorders because, for example, the inhalation of the pulmonary surfactant can relieve a fit of allergy-induced asthma (e.g., Babu, K. S., et al., Eur. Respir. J., 21:1046-1049, 2003).
Fujiwara et al. have reported about an effect of the artificial pulmonary surfactant on human RDS and succeeded for the first time in the world in the development of an agent for curing RDS (“Surfacten®”) (e.g., Japanese Patent Publication No. S61-9925). Surfacten® is an agent which consists of phospholipids (75.0-95.5%), neutral lipids (1.8-14.0%) and proteins (5% or less), which is prepared by extracting the active pulmonary surfactant ingredient from the bovine lung. As the protein and the phospholipid (particularly DPPC) to be used therefor are expensive, the resulting pulmonary surfactant, Surfacten®, is also so expensive that the issue is a difficulty in the application of Surfacten® to a very limited field.
The incidence of ARDS is reported to be 15 to 20 cases out of the population of 100,000. Even if the basic diseases could be cured, however, it is also reported that the exitus may unfortunately be caused to occur in many cases due to damages of the lung caused by the artificial ventilation or oxygen used for the treatment in the acute stage and the mortality of ARDS is as extremely high as approximately 50%. It is further reported that the administration of large amounts of the artificial pulmonary surfactant at the early stage of ARDS can improve the pulmonary functions and minimizing the damages of the lung reducing the mortality up to 20% (e.g., Gregory, T. J., et al., Am. J. Respir. Crit. Car. Med., 155, 1309-1315, 1997). The pulmonary surfactant is of great significance for the treatment of severe respiratory insufficiency and at the same time it is effective for removing phlegm and relieving a fit of asthma in the manner as described above.
From the above, many medical doctors involved in the treatment of respiratory diseases have pointed out the possibilities of application of the pulmonary surfactant to many different kinds of pulmonary diseases; however, the pulmonary surfactant is so very expensive that the application of Surfacten® to RDS only is currently covered by the health insurance in Japan. A further issue is that Surfacten® is a bovine protein preparation so that it still has the possibility of infection due to its antigenicity and unknown antigenicity and the problem with bovine spongiform encephalopathy for example still remains unsolved. In this sense, the development of an artificial pulmonary surfactant which can be prepared at lower costs and has no side effects has been demanded.
In order to meet such a demand, Cochrane et al. reported a synthetic surfactant for the first time in 1991 (e.g., Cochrane C. G. and Revak S. D., Science, 254, 566-568, 1991). The synthetic surfactant which in turn is currently under clinical investigation is a lipid-peptide complex (Surfaxin) composed of 21 amino acids (KL4) and a lipid and is expected to become a novel agent for the treatment of ARDS (e.g., Wiswell, T., et al., Pediatrics, 109, 1081-1087, 2002).
In addition, there are disclosed a pulmonary surfactant composed of a mixture of a synthetic peptide with a lipid and an agent for the treatment of respiratory distress syndromes which contains the pulmonary surfactant as an active ingredient (e.g., Japanese Patent Application Publication No. 05-294,996; WO 95/15,980). More specifically, the pulmonary surfactant is composed of choline phosphoglyceride, a synthetic peptide having a particular amino sequence, an acidic phospholipid and an aliphatic acid.